Heck Coupling Using SiliaCat DPP-Pd & S-Pd

The Heck reaction, also known as the Mizoroki-Heck reaction, is the coupling of a halide with an alkene in the presence of a base and a palladium catalyst. This coupling allows a substitution reaction on alkenes and is of great importance in pharmaceutical research. We determined that the best catalyst for this reaction is SiliaCat DPP-Pd. It showed good reactivity for aryl iodides, bromides and chlorides.

Note: SiliaCat Pd0 results were not available at the time of printing. Contact us for details.

Base and Solvent Effects

The Heck coupling between iodobenzene and styrene was used to evaluate the influence of solvent and base. The best combinations are KOAc/DMF, Et3N/MeCN and Pr3N/neat. Using these systems, high yields and great selectivity in favor of product A were obtained.

Base and Solvent Effects (SiliaCat DPP-Pd)

SiliaCat
(mol %)

Base

Solvent
(0.4 M)

Time
(h)

Conversion
A / B / C (%)

0.5

KOAc

DMF

24

100 (90 / 9.5 / 0.5)

0.5

Na2CO3

DMF

24

67 (62 / 47 / 0)

0.1

Et3N

MeCN

24

93 (77 / 6 / 11)

0.1

Et3N

H2O

24

75 (70 / 5 / 0)

0.1

Pr3N

(neat)

20

100 (95 / 5 / 0)

Catalytic Performance and Comparison vs Homogeneous Catalyst

SiliaCat DPP-Pd is a very efficient catalyst for the Heck coupling and allows greater selectivity over homogeneous Pd catalyst (TPP is required). In addition to higher yield of the desired product, the catalyst left minimal residual Pd, TPP or TPPO in solution that would have otherwise required the use of a metal scavenger, chromatography or trituration to remove.

Catalytic Performance and Comparaison vs Homogeneous

Substrate

SiliaCat DPP-Pd
(mol %)

Base

Solvent
(0.4 M)

Conversion
A / B / C (%)

Phosphine Leaching (ppm)

R

X

4-CN

Br

0.25

NaOAc

DMF

100 (95 / 5 / -)

-

4-NO2

Br

0.25

NaOAc

DMF

99 (97 / 2 / -)

-

2-CH3

Br

0.25

Et3N

MeCN

71 (67 / 5 / -)

-

4-OMe

I

0.25

Et3N

MeCN

75 (60 / 15 / -)

-

H

I

0.1

Et3N

MeCN

100 (98 / 2 / -)

0

H

I

1.0 Pd(OAc)2 PPh3

Et3N

MeCN

100 (70 / 22 / 8)

6,030

Substrate Scope, Leaching and Microwave Compatibility

SiliaCat catalysts are efficient in the Heck coupling with different substrates. In all cases, conversion and selectivities were excellent. Leaching results were all below FDA regulations, and no further metal removal was needed. Microwave technology allows faster kinetics with good yields.

Substrate Scope, Leaching and Microwave (MW) Compatibility

Rn

Mode

SiliaCat DPP-Pd

SiliaCat S-Pd

mol %

Time

Temp

Conv. / Sel. (%)

Leaching (ppm)

mol %

Time

Temp

Conv. / Sel. (%)

Leaching (ppm)

1

Batch

0.5

24 h

120°C

100 / 97

-

0.5

24 h

120°C

98 / 92

-

MW

0.2

10 m

125°C

93 / 85

P: 0.3, Pd: 0.02, Si: 0.8

0.2

15 m

125°C

97 / 93

Pd: 3.8, Si: 1.9

2

Batch

0.2

24 h

135°C

100 / 98

-

0.25

24 h

120°C

85 / 75

-

MW

0.2
0.5

10 m
30 m1

125°C
150°C

92 / 81
99 / 931

-
P: 0.7, Pd: 0.02, Si: 1.6

0.2

15 m

125°C

87 / 76

Pd: 0.3, Si: 0.8

Heck Coupling Typical Experimental Procedure

Conventional Experimental Conditions

Reaction - All products except the catalyst are added to a round bottom flask equipped with a condenser and a magnetic stirrer. Bring mixture to reflux (MeCN) or to 120°C (DMF or NMP) and after 10 minutes (when solution is homogeneous) add the desired quantity of catalyst.

Microwave Conditions

Reaction - All products are added to a microwave tube equipped with a magnetic stirrer. Set microwave conditions to:

Power: 100 W (I-) or 200 W (Br-, Cl-)

Pressure: 150 psi (I-) or 200 psi (Br-, Cl-)

Temperature: 100°C (I-) or 125°C (Br-, Cl-)

Reaction Time: 10 min (I-) or 15 min (Br-, Cl-)

Work-up

Once the reaction is complete (determined by TLC or GC-MS), follow the same work-up procedure as for Suzuki coupling conventional experimental conditions as they are applicable to microwave conditions.